Autoimmune diabetes is characterized by the selective destruction of the insulin secreting ?-cells of the pancreas. Environmental factors, such as viral infections, have been proposed to initiate ?-cell damage during autoimmune diabetes development. Encephalomyocarditis virus (EMCV) induces diabetes in susceptible strains of mice. EMCV-stimulated diabetes induction is associated with macrophage activation and the expression of inflammatory mediators interleukin-1 (IL-1?) and nitric oxide. The broad goals of this research are to identify mechanisms by which virus infections contribute to ?-cell damage. The C-C chemokine receptor CCR5 has been identified as a signaling receptor activated in response to EMCV infection and is responsible for regulating expression of IL-1?, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in macrophages. While CCR5 participates in regulating macrophage activation in response to EMCV infection, non-leukocyte cell populations (including ?-cells) do not express this receptor. Consistent with a lack of ?-cell expression of CCR5 is the identification of two micro-RNAs that reside within type 1 diabetes susceptibility loci that are predicted to target CCR5. CCR5 has also been previously identified in Genomic Wide Association Studies (GWAS) to be in a susceptibility locus of type 1 diabetes. Therefore, this research proposal will examine CCR5 as a potential susceptibility gene to virus-induced diabetes by studying the CCR5-dependent signaling pathways required for macrophage activation, the cellular regulation of CCR5 expression by micro-RNAs, and whether CCR5 contributes to susceptibility to EMCV-induced diabetes. Aim 1 will test the hypothesis that Akt and mammalian target of rapamycin complex 1 (mTORC1), in a CCR5-dependent manner, regulate the activation of macrophages in response to EMCV infection. Mouse models lacking CCR5 will be generated to test the potential role of CCR5 in regulating mouse susceptibility to EMCV-induced diabetes. Aim 2 will test the hypothesis that micro-RNAs limit the expression of CCR5 in ?-cells and thereby attenuate the expression of inflammatory mediators known to cause ?-cell damage in response to EMCV infection. Experiments will determine the role of micro-RNA(s) in preventing CCR5 expression in ?-cells. The potential role of CCR5 expression in ?-cells as a mechanism to increase ?-cell susceptibility to virus- induced death will also be examined, as aberrant CCR5 expression may lead to ?-cell iNOS expression during EMCV infection and thus potentiation of virus-induced damage. This proposal will elucidate mechanisms by which CCR5 controls expression of soluble mediators known to damage ?-cells, by studying mechanisms of macrophage activation in response to viral infection and how micro-RNAs may suppress ?-cell expression of CCR5. These results may provide information on precipitating events associated with the induction of diabetes.